That stimulants can be associated with a paranoid psychosis in otherwise normal individuals is frequently offered as evidence for the involvement of the dopamine (DA) system in psychotic illness. One animal paradigm designed to study this phenomenon has been the chronic administration of amphetamines (AMPH), agents known to enhance release and block uptake of DA. In numerous animal studies, infusion of relatively low doses of meth-AMPH has been associated with depletion of DA and its metabolites, a decrease in tyrosine hydroxylase, a decline in DA receptors, and structural changes consistent with neurotoxicity. These changes have been found most frequently in the striatum, olfactory tubercle, and cortex. To further examine this mechanism, we chose to study the biochemical effects of cocaine, a stimulant known to inhibit the uptake of central catecholamines. We chronically administered cocaine (10 mg/kg) or saline twice daily to rats by intraperitoneal injection for 1, 2, and 3 weeks. In a series of experiments, the frontal cortex, nucleus accumbens, caudate nucleus, and hypothalamus were removed at intervals ranging from 1 hour to 3 months after the last dose. Norepinephrine, DA, and their metabolites were measured by mass-fragmentography. We found a persistent, significant reduction in dopamine and in the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the frontal cortex and hypothalamus, an observation lending further evidence to the links between stimulants and persistent dopamine deficit states.